Structural determinants of peripheral O-arylcarbamate FAAH inhibitors render them dual substrates for Abcb1 and Abcg2 and restrict their access to the brain

Abstract

The blood-brain barrier (BBB) is the main entry route for chemicals into the mammalian central nervous system (CNS). Two transmembrane transporters of the ATP-binding cassette (ABC) family – Breast Cancer Resistance Protein (ABCG2 in humans, Abcg2 in rodents) and P-glycoprotein (ABCB1 in humans, Abcb1 in rodents) – play a key role in mediating this process. Pharmacological and genetic evidence suggests that Abcg2 prevents CNS access to a group of highly potent and selective O-arylcarbamate fatty-acid amidohydrolase (FAAH) inhibitors, which include the compound URB937 (cyclohexylcarbamic acid 3′-carbamoyl-6-hydroxybiphenyl-3-yl ester). To define structure-activity relationships of the interaction of these molecules with Abcg2, in the present study we tested various peripherally restricted and non-restricted O-arylcarbamate FAAH inhibitors for their ability to serve as transport substrates in monolayer cultures of Madin-Darby Canine Kidney-II (MDCKII) cells over-expressing Abcg2. Surprisingly, we found that the majority of compounds tested – even those able to enter the CNS in vivo – were substrates for Abcg2 in vitro. Additional experiments in MDCKII cells overexpressing ABCB1 revealed that only those compounds that were dual substrates for ABCB1 and Abcg2 in vitro were also peripherally restricted in vivo. The extent of such restriction seems to depend upon other physicochemical features of the compounds, in particular the polar surface area. Consistent with these in vitro results, we found that URB937 readily enters the brain in dual knockout mice lacking both Abcg2 and Abcb1, whereas it is either partially or completely excluded from the brain of mice lacking either transporter alone. The results suggest that Abcg2 and Abcb1 act together to restrict the access of URB937 to the CNS.

Pharmacokinetics, pharmacodynamics and safety studies on URB937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats

“…The mechanism underlying this peripheral segregation has been shown to involve two distinct transmembrane transporters that belong to the ATP‐binding cassette family: Abcg2 (breast cancer resistance protein) and Abcb1 (P‐glycoprotein) . These transporters are highly expressed in cells of the blood–brain barrier and may act in concert to restrict the access of URB937 to the brain and spinal cord . Supporting this idea, in the present report we confirmed that URB937 does not enter the CNS when administered at therapeutically effective doses (Figures a and b).…”

“…Confirming previous work, we found that the compound is excluded from the CNS (Figures and ). The mechanism underlying this peripheral segregation has been shown to involve two distinct transmembrane transporters that belong to the ATP‐binding cassette family: Abcg2 (breast cancer resistance protein) and Abcb1 (P‐glycoprotein) . These transporters are highly expressed in cells of the blood–brain barrier and may act in concert to restrict the access of URB937 to the brain and spinal cord .…”

“…One way to explore the therapeutic potential of peripheral endocannabinoid‐mediated analgesia is to use CNS‐impenetrant inhibitors of the anandamide‐degrading enzyme, fatty acid amide hydrolase (FAAH) . Molecules like the O‐aryl‐carbamate derivative URB937 inhibit FAAH activity outside the brain and spinal cord, from which they are actively extruded by ATP‐cassette membrane transporters present in the blood–brain barrier . The availability of these probes has allowed researchers to show that blockade of peripheral FAAH activity attenuates nociceptive responses in various animal models of acute and chronic pain, through a mechanism that requires elevation of anandamide levels and subsequent activation of CB 1 receptors outside the CNS …”

A novel paclitaxel-loaded poly(D,L-lactide-co-glycolide)-Tween 80 copolymer nanoparticle overcoming multidrug resistance for lung cancer treatment

“…31 Various studies have also demonstrated that Tween 80-based NPs could inhibit the exocytosis of p-gp, increasing the concentration of chemotherapeutics in tumor cells. 32 In this study, PLGA-Tween 80 conjugate was first synthesized via a one-step esterification reaction. The chemical structure of PLGA-Tween 80 was confirmed by 1 H-NMR and FTIR spectra.…”

Gyógyszertranszporterek szerepe a központi idegrendszerben

“…Az apicalistól a basolateralis és az ellentétes irányú transzportot értékelték inhibitorok jelenlétében és hiányában [17]. Moreno-Sanz és mtsai [18] Bcrp-t overexpresszáló MDCKII sejtvonalon vizsgálták zsírsav-amidohidroláz-gátlók penetrá cióját. Minocha és mtsai [19] szintén MDCKII sejteken tanulmányozták a P-gp-és Bcrp-moduláció hatásait.…”